title: DXR inhibition by potent mono- and disubstituted fosmidomycin analogues.
abstract: The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM.
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University , Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Jansson
authors.forename: Anna
authors.initials: A
authors.lastname: Więckowska
authors.forename: Christofer
authors.initials: C
authors.lastname: Björkelid
authors.forename: Samir
authors.initials: S
authors.lastname: Yahiaoui
authors.forename: Sanjeewani
authors.initials: S
authors.lastname: Sooriyaarachchi
authors.forename: Martin
authors.initials: M
authors.lastname: Lindh
authors.forename: Terese
authors.initials: T
authors.lastname: Bergfors
authors.forename: Shyamraj
authors.initials: S
authors.lastname: Dharavath
authors.forename: Matthieu
authors.initials: M
authors.lastname: Desroses
authors.forename: Surisetti
authors.initials: S
authors.lastname: Suresh
authors.forename: Mounir
authors.initials: M
authors.lastname: Andaloussi
authors.forename: Rautela
authors.initials: R
authors.lastname: Nikhil
authors.forename: Sharma
authors.initials: S
authors.lastname: Sreevalli
authors.forename: Bachally R
authors.initials: BR
authors.lastname: Srinivasa
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
authors.forename: T Alwyn
authors.initials: TA
authors.lastname: Jones
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Mowbray
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D006877:Hydroxamic Acids; D005578:Fosfomycin; C024640:fosmidomycin; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases